US3162680A - 1-(5-glutamyl)-2-(phenyl)-lower alkyl hydrazines - Google Patents
1-(5-glutamyl)-2-(phenyl)-lower alkyl hydrazines Download PDFInfo
- Publication number
- US3162680A US3162680A US781422A US78142258A US3162680A US 3162680 A US3162680 A US 3162680A US 781422 A US781422 A US 781422A US 78142258 A US78142258 A US 78142258A US 3162680 A US3162680 A US 3162680A
- Authority
- US
- United States
- Prior art keywords
- hydrazine
- phenyl
- groups
- group
- acyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- -1 alkyl hydrazines Chemical class 0.000 title description 63
- 150000001875 compounds Chemical class 0.000 claims description 20
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Substances NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 238000004821 distillation Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- QCCDLTOVEPVEJK-UHFFFAOYSA-N phenylacetone Chemical compound CC(=O)CC1=CC=CC=C1 QCCDLTOVEPVEJK-UHFFFAOYSA-N 0.000 description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 229960002748 norepinephrine Drugs 0.000 description 6
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 229940076279 serotonin Drugs 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 150000002429 hydrazines Chemical class 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000008499 blood brain barrier function Effects 0.000 description 4
- 210000001218 blood-brain barrier Anatomy 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 4
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 4
- 229910003446 platinum oxide Inorganic materials 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CAHGPINWWFMBKO-UHFFFAOYSA-N 2-hydroxy-2,2-diphenylacetohydrazide Chemical compound C=1C=CC=CC=1C(O)(C(=O)NN)C1=CC=CC=C1 CAHGPINWWFMBKO-UHFFFAOYSA-N 0.000 description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 2
- NYMGNSNKLVNMIA-UHFFFAOYSA-N Iproniazid Chemical compound CC(C)NNC(=O)C1=CC=NC=C1 NYMGNSNKLVNMIA-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229940125717 barbiturate Drugs 0.000 description 2
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 150000007857 hydrazones Chemical class 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 229940070023 iproniazide Drugs 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- HACMXPVQBHWNHX-VKHMYHEASA-N (4s)-4-amino-5-hydrazinyl-5-oxopentanoic acid Chemical compound NNC(=O)[C@@H](N)CCC(O)=O HACMXPVQBHWNHX-VKHMYHEASA-N 0.000 description 1
- YFKBXYGUSOXJGS-UHFFFAOYSA-N 1,3-Diphenyl-2-propanone Chemical compound C=1C=CC=CC=1CC(=O)CC1=CC=CC=C1 YFKBXYGUSOXJGS-UHFFFAOYSA-N 0.000 description 1
- MIRNHGCBMVDSEI-UHFFFAOYSA-N 1-(4-chlorophenyl)butan-2-one Chemical compound CCC(=O)CC1=CC=C(Cl)C=C1 MIRNHGCBMVDSEI-UHFFFAOYSA-N 0.000 description 1
- NFKAWBGFIMBUMB-UHFFFAOYSA-N 1-phenylpentan-2-one Chemical compound CCCC(=O)CC1=CC=CC=C1 NFKAWBGFIMBUMB-UHFFFAOYSA-N 0.000 description 1
- ZWLWYLRWALOGBO-UHFFFAOYSA-N 1-phenylpropan-2-yl-(pyridin-1-ium-2-carbonylamino)azanium;dichloride Chemical compound [Cl-].[Cl-].C=1C=CC=[NH+]C=1C(=O)N[NH2+]C(C)CC1=CC=CC=C1 ZWLWYLRWALOGBO-UHFFFAOYSA-N 0.000 description 1
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 1
- LIUCWHQVLKSECA-UHFFFAOYSA-N 2-hydroxyacetohydrazide Chemical compound NNC(=O)CO LIUCWHQVLKSECA-UHFFFAOYSA-N 0.000 description 1
- FPTCVTJCJMVIDV-UHFFFAOYSA-N 2-phenylacetohydrazide Chemical compound NNC(=O)CC1=CC=CC=C1 FPTCVTJCJMVIDV-UHFFFAOYSA-N 0.000 description 1
- DIBSCKQIZZVKMG-UHFFFAOYSA-N 2-phenylbutanal Chemical compound CCC(C=O)C1=CC=CC=C1 DIBSCKQIZZVKMG-UHFFFAOYSA-N 0.000 description 1
- UIXIZFIUMREAFZ-UHFFFAOYSA-N 2-phenylpentanal Chemical compound CCCC(C=O)C1=CC=CC=C1 UIXIZFIUMREAFZ-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- YGCZTXZTJXYWCO-UHFFFAOYSA-N 3-phenylpropanal Chemical compound O=CCCC1=CC=CC=C1 YGCZTXZTJXYWCO-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- WVYWICLMDOOCFB-UHFFFAOYSA-N 4-methyl-2-pentanol Chemical compound CC(C)CC(C)O WVYWICLMDOOCFB-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 102000010909 Monoamine Oxidase Human genes 0.000 description 1
- 108010062431 Monoamine oxidase Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- ZGUGWUXLJSTTMA-UHFFFAOYSA-N Promazinum Chemical compound C1=CC=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZGUGWUXLJSTTMA-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 1
- 125000005530 alkylenedioxy group Chemical group 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 150000007514 bases Chemical class 0.000 description 1
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 1
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960002155 chlorothiazide Drugs 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- LJQKCYFTNDAAPC-UHFFFAOYSA-N ethanol;ethyl acetate Chemical compound CCO.CCOC(C)=O LJQKCYFTNDAAPC-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical compound [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000005059 halophenyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000006996 mental state Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 239000000712 neurohormone Substances 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- 229960000964 phenelzine Drugs 0.000 description 1
- VXTWEDPZMSVFEF-UHFFFAOYSA-N pheniprazine Chemical compound NNC(C)CC1=CC=CC=C1 VXTWEDPZMSVFEF-UHFFFAOYSA-N 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N phenyl propionaldehyde Natural products CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 1
- 229940100595 phenylacetaldehyde Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229960003598 promazine Drugs 0.000 description 1
- DXGIRFAFSFKYCF-UHFFFAOYSA-N propanehydrazide Chemical compound CCC(=O)NN DXGIRFAFSFKYCF-UHFFFAOYSA-N 0.000 description 1
- BAQLNPIEFOYKNB-UHFFFAOYSA-N pyridine-2-carbohydrazide Chemical compound NNC(=O)C1=CC=CC=N1 BAQLNPIEFOYKNB-UHFFFAOYSA-N 0.000 description 1
- KFUSANSHCADHNJ-UHFFFAOYSA-N pyridine-3-carbohydrazide Chemical compound NNC(=O)C1=CC=CN=C1 KFUSANSHCADHNJ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
Definitions
- Y is a straight or branched alkylene group, advisably of 12 or less carbons although it generally is of 5 or less carbons, such as of the group:
- R is hydrogen or a substituent of the group consisting of:
- Aryl groups such as the phenyl group and nuclear substituted phenyl groups such as halophenyl, alkoxyphenyl, hydroxyphenyl, o-acyloxyphenyl, aminophenyl, acetylaminophenyl, diand trialkoxyphenyl groups and lower alkylenedioxyphenyl groups and especially the 3,4-methylenedioxyphenyl, o-acetoxyphenyl, dimethoxyphenyl, p aminophenyl, p acetylaminophenyl, 3,4,5-trimethoxyphenyl, dirnethoxyphenyl, p-chlorophenyl, p-hydroxyphenyl, p-methoxyphenyl and o-methylphenyl groups.
- phenyl group and nuclear substituted phenyl groups such as halophenyl, alkoxyphenyl, hydroxyphenyl, o-acyloxyphenyl, aminophenyl, acety
- Aralkyl groups such as phenyl-lower alkyl groups including the benzyl, phenethyl, phenylisopropyl, phenylbutyl, o-methylbenzyl, Z-propenylphenyl, 2-phenyl-l-aminoethyl, 2-(3,4-dihydroxyphenyl)-l-aminoethyl, 3-phenyl-2-amino-2-propyl 2-( 3,4 methylenedioxyphenyl) 1 aminoethyl, and
- Heterocyclic groups such as the pyridyl, quinolyl, cinchonyl, 4-pyridyl, 3-pyridyl, thiazolyl, thienyl, 3-indolyl, Z-indolyl, 5-hydroXy-3-indolyl, S-methoXy-l-benZyl-3-indolyl, 1 benzyl-2,5-dimethoxy-3- indolyl, isoXazolyl, imidazolyl, 2-(3-indolyl)-1- amino-ethyl, S-keto-Z-pyrrolidinyl, S-pyrrolidyl and l-methyl-4-phenyl-4-piperidyl groups.
- Alkynyl groups and particularly lower alkynyl groups such as the propargyl group.
- Aminoalkyl groups such as aminomethyl, fl-arni noethyl, alpha-aminoethyl, 3-(methylmercapto)-laminopropyl, 4-methyl-l-aminobutyl, 3-hydroXy-laminopropyl and 3-methyl-3-hydroxy-l-ammopro- Py
- Omega-carboxy-(amino)-alkyl groups such as Z-carboxy-l-aminoethyl, 3-carboxy-l-aminopropyl,
- Carboxyalkyl groups such as the carboxy-lower alkyl groups including the carboxyethyl group.
- R is hydrogen or at least one nuclear substituent on the phenyl group such as a:
- Aryl group such as the phenyl group.
- Aryloxy group such as the phenoxy group.
- Aralkyl group as the benzyl or phenethyl group.
- Some specific compounds which may be used as described are l-phenylmethyl-Z-acetyl hydrazine, l-phenylethyl-2-propionyl hydrazine, l-phenylpropyl-Z-benzoyl hydrazine, 1-phenylisopropyl-2-cyclohexanecarboxyl hydrazine, 1-p-chlorophenylmethyl-Z-phenylacetyl hydrazine, lp-methoxyphenylhexyl-Z-p-chlorophenylpropionyl hydrazine, 1-phenylisopropyl-Z-isonicotinyl hydrazine, l-phenylbutyl-Z-(Z-pyrrolecarboxyl)hydrazine, 1 phenyloctyl 2- nicotinyl hydrazine, 1-phenylethyl-2-(2-pyrazinylcarboxy
- the most potent monoamine oxidase inhibitors of Formula I are those in which Y has no more than three carbons between the phenyl and hydrazine moieties.
- These l-phenylalkyl-2-acyl hydrazines have an etfect on the heart.
- the compounds are useful in the treatment of aperson in a'state of shock.
- hypotensor agents when administered to humans and thus are useful in the treatment of hypertension. In the dog, however, they raise the blood pressure.
- N- pyrrolidone-Z-carboxyl) N-(1-phenyl-2-propyl)-hydrazine is particularly active and, in addition, is faster acting in humans than iproniazid.
- the compounds of this invention are useful for potentiating other therapeutic agents, such as phenothiazine tranquilizers like promazine and chloropromazine.
- the compounds of this invention are themselves potentiated by chlorothiazide so that a greater hypotensor activity is obtained.
- the l-phenylalkyl-Z-acyl hydrazines may be administered to animals and humans as pure compounds. It is advisable, however, to first combine one or more of the novel compounds with a suitable pharmaceutical carrier to attain a more satisfactory size to dosage relationship.
- compositions which are liquid or solid may be used.
- the preferred liquid carrier is water. Flavoring materials may be included in the solutions as desired.
- Solid pharmaceutical carriers such as starch, sugar talc and the like may be used to form powders.
- the powders may be used as such for direct administration to a patient or, instead, the powders may be added to suitable foods and liquids, including water, to facilitate administration.
- the powders may also be used to make tablets, or to fill gelatin capsules.
- Suitable lubricants like magnesium stearate, binders such as gelatin, and disintegrating agents like sodium carbonate in combination with citric acid may be used to form the tablets.
- Unit dosage forms such as tablets and capsules may contain any suitable predetermined amount of one or more of the l-phenylalkyl-Z-acyl hydrazines as a nontoxic acid addition salt and may be administered one or more at a time at regular intervals. Such unit dosage forms, however, should generally contain a cencentration of 0.1% to 10% by weight of one or more of the active hydrazines.
- Dosages of from about 1 mg. to 50 mg. may be administered to obtain the stated activities. However, the recommended dosages are from 3 to 12 mg. daily. Larger dosages may be administered on an interrupted schedule but generally not more than 50 mg. and preferably not more than 25 mg. is administered daily.
- a typical tablet may have the composition:
- N- 5-pyrrolidone-Z-carboxyl) -N'-( l-phenyl- 2-propyl)-hydrazine may be used in this procedure to form tablets containing it as the active ingredient.
- Capsules may be prepared by filling No. 3 hard gelatin capsules with the following ingredients, thoroughly mixed:
- the oral route is preferred for administering the active l-phenylalkyl-Z-acyl hydrazines.
- one or more of the l-phenylalkyl-2-acyl hydrazines is administered simultaneously with, or concomitantly to, the administration of either tryptophan and/or phenylalanine to an animal or human.
- Tryptophan passes the blood-brain barrier and is converted in the brain to serotonin. Serotonin is not administered directly since it cannot pass the blood-brain barrier.
- phenylalanine passes the blood-brain barrier and is converted in the brain to norepinephrine. Norepinephrine itself will not pass the blood-brain barrier so it is not given directly.
- the monoamine oxadase inhibitory property of the hydrazine retards or prevents the degradation of serotonin and/or norepinephrine which 6 are produced in the brain from the said amino acids.
- the serotonin and norepinephrine levels are thus not only raised but are maintained at the increased level by the described treatment.
- Any suitable amounts of tryptophan and/ or phenylalanine may be administered since these materials are nontoxic.
- One or more of these materials advisably combined with one or more of the active hydrazines into suitable pharmaceutical formulations.
- This method of preparing the l-phenylalkyl-Z-acyl hydrazines comprises reacting the hydrazine with a phenylalkyl ketone or aldehyde to form a 1-ara1kylidenyl-2-acyl hydrazine and reducing the hydrazone to the desired l-phenylalkyl-Z-acyl hydrazines.
- This process may be represented as follows:
- phenylalkyl ketones or aldehydes which may be used in this process are phenylacetaldehyde, phenylpropionaldehyde, phenylbutyraldehyde, phenylacetal, phenylvaleraldehyde, phenylethanone, phenylacetone, 1,3- diphenyl 2 propanone, phenylpentanone and p-chlorophenylbutanone and similar compounds containing one or more nuclear groups on the phenyl group, such as represented by R in the Formula I.
- acyl hydrazines which may be used in the process are'acetyl hydrazine, propionyl hydrazine, benzoyl hydrazine, cyclohexanecarboxyl hydrazine, phenylacetyl hydrazine, isonicotinyl hydrazine, pyrrolcarboxyl hydrazine, nicotinyl hydrazine, benziloyl hydrazine, dicyclohexylglycolyl hydrazine and the like.
- Reaction between the phenylalkyl ketone or aldehyde and the acyl hydrazine is conveniently efiected by contacting the reactants in the presence of water or a lower alcohol.
- the reaction proceeds at room temperature although slightly elevated temperatures such as the reflux temperature may be employed to increase the rate of reaction.
- the product generally an oil as the free base, may be salted out with an alkali metal hydroxide and extracted with a water immiscible organic solvent such as ether.
- a water immiscible organic solvent such as ether.
- the product is readily isolated by distillation under reduced pressure.
- the intermediate hydrazones may be reduced to the corresponding hydrazines by use of a suitable reducing agent.
- a suitable reducing agent Lithium alumirnun hydride may be used although catalytic hydrogenation is recommended. With lithium aluminum hydride, the reduction may be conveniently eflected by intimately combining the reactants in an inert organic solvent such as anhydrous ether, diox-ane, or tetrahydrofuran. Elevated temperatures such as the reflux temperature enhance the reaction. At reflux temperature, from 1 to 8 hours is usually suificient to substantially complete the reaction. After the reaction is terminated, water may be added to the mixture to decompose excess lithium aluminum hydride. To recover the product, the organic phase is separated and the aqueous residue extracted with the same solvent. The organic phase and extracts then may be combined, dried, and the product distilled.
- an inert organic solvent such as anhydrous ether, diox-ane, or tetrahydrofuran. Elevated
- Catalytic reduction is readily achieved using catalysts such as rhodium, platinum oxide, palladium and the like in solvents such as methanol, ethanol, tctrahydroturan,
- Raney nickel is not a particularly suitable catalyst since undue cleavage occurs.
- Hydrogen pressures of about 50 to 3000 p.s.i. may be used.
- the temperature of reduction may be room temperature of increased temperatures such as up to C.
- Hydrazines such as those named above, may be formed in this way.
- EXAMPLE 5 1 (5 -Pyrr0lid0ne -2 '-Carb0xyl2-Benzylidenyl H ydrazine 7
- EXAMPLE 6 1 '-Pyrr0lidone) -2-Carboxyl] -2-Benzyl H ydrazine
- a methanol solution containing 0.10 mole of the benzylidene derivative of Example 5 was subjected to hydrogenation at 40 p.s.i. of hydrogen in the presence of 0.1 g. of platinum oxide catalyst. Hydrogenation was discontinued as soon as the theoretical amount of hydrogen had been absorbed, to prevent cleavage of the benzyl group.
- the catalyst was removed by filtration and the solvent removed by distillation. The residue was an oil which did not readily crystallize.
- EXAMPLE 7 J-(S-Glutamyl)-2-(AIpl1a-Plzenyl)-Ethyl Hydrazine
- Ethyl glutamate was converted to the hydrazide in the usual manner.
- the hydrazide was reacted with acetophenone by mixing equirnolar quantities of glutamic acid hydrazide with acetophenone in methylisobutylcarbinol and refluxing the mixture for several hours.
- the solvent was removed by distillation in vacuo and the residue taken up in methanol.
- the methanol solution was subjected to hydrogenation in the usual manner being careful, however, to allow only the theoretical amount of hydrogen to be absorbed.
- the hydrogenation catalyst was removed by filtration and the filtrate concentrated in vacuo.
- the residual product was a low melting solid.
- Example 2 l-benzoyl hydrazine was reacted with l-phenyl-Z-propanone following the method of Example 1 and the resulting phenylisopropylidene derivative reduced catalytically as in Example 2 to yield the desired product.
- EXAMPLE 11 The acyl hydrazone (12.95 g.) of Example 10 was reduced with 0.50 g. of PtO in 200 cc. of ethanol at 60 lbs. of hydrogen. The solvent was removed by distillation and the residue crystallized from ether. The solid was recrystallized from acetonitrile, M.P. 160 C.
- EXAMPLE 14 1-Nicotinyl-2-Phenylis0pr0pylidenyl H ydrazine
- EXAMPLE 16 l-Pic0linyl-2-Phenylisopropylidenyl H ydrazine This compound was prepared from picolinic acid hydrazide and 1-phenyl-2-propanone by the procedure of Example 1; yield M.P. 145146 C.
- the dihydrochloride salt melted at 189-190 C.
Description
United States Patent 3,162,68t9 1-(5-GLUTAMYE)-Z-(FHENYD-LGWER ALKYL HYDRAZWES .lohn H. Biol, Milwaukee, Wis, assignor, by mesne assignments, to Colgate-Palmolive Company, a corporation of Delaware No Drawing. Filed Dec. 19, $58, Ser. No. 781,422 4 tllaims. (Cl. 26tl--518) This invention relates to hydrazine derivatives. More particularly, this invention is concerned with l-phenylalkyl-Z-acyl hydrazines and the use of these compounds as psychotherapeutic agents. The invention is also con cerned with novel pharmaceutical compositions containing a l-phenylalkyl-Z-acyl hydrazine.
This application is a continuation-in-part of my copending application Serial No. 716,878, filed Februar 24, 1958, now abandoned.
It has now been discovered according to the present invention that 1-phenylalkyl-2 acyl hydrazines of the formula s wherein Y is an alkylene group,
; chemical transmitters in, or stimulants of, the central nervous system. A deficiency of available serotonin or norepinephrine in the brain, such as can be caused by metabolism or degradation of these agents by monoamine oxidase, may result in parasympathetic predominance present in depressed mental states. By preventing or retarding destruction of serotonin and norepinephrine through the use of l-phenylalkyl-Z-acyl hydrazines the levels of these neurohumoral agents present in the body are maintained higher for longer periods of time so that sympathetic characteristics such as increased awareness and motility result.
Representative of some of the l-phenylalkyl-Z-acyl hydrazines of the formula (H) @Y-NHNHCR R1 which have the described psychotherapeutic activities, ad-
visably as nontoxic acid addition salts, are compounds in which Y, R and R have the following significance:
3 ,162,686 Patented Dee. 22, 1964 (1) Y is a straight or branched alkylene group, advisably of 12 or less carbons although it generally is of 5 or less carbons, such as of the group:
(2) R is hydrogen or a substituent of the group consisting of:
(a) Alkyl groups from 1 to 15 carbons and advisably lower alkyl groups such as methyl, ethyl, propyl, butyl, isopropyl and the like.
([2) Aryl groups such as the phenyl group and nuclear substituted phenyl groups such as halophenyl, alkoxyphenyl, hydroxyphenyl, o-acyloxyphenyl, aminophenyl, acetylaminophenyl, diand trialkoxyphenyl groups and lower alkylenedioxyphenyl groups and especially the 3,4-methylenedioxyphenyl, o-acetoxyphenyl, dimethoxyphenyl, p aminophenyl, p acetylaminophenyl, 3,4,5-trimethoxyphenyl, dirnethoxyphenyl, p-chlorophenyl, p-hydroxyphenyl, p-methoxyphenyl and o-methylphenyl groups.
(0) Aralkyl groups such as phenyl-lower alkyl groups including the benzyl, phenethyl, phenylisopropyl, phenylbutyl, o-methylbenzyl, Z-propenylphenyl, 2-phenyl-l-aminoethyl, 2-(3,4-dihydroxyphenyl)-l-aminoethyl, 3-phenyl-2-amino-2-propyl 2-( 3,4 methylenedioxyphenyl) 1 aminoethyl, and
l-phenyl-Z-hydroxyethyl groups.
(d) Cycloalkyl groups such as the cyclopentyl and cyclohexyl groups.
(e) Heterocyclic groups such as the pyridyl, quinolyl, cinchonyl, 4-pyridyl, 3-pyridyl, thiazolyl, thienyl, 3-indolyl, Z-indolyl, 5-hydroXy-3-indolyl, S-methoXy-l-benZyl-3-indolyl, 1 benzyl-2,5-dimethoxy-3- indolyl, isoXazolyl, imidazolyl, 2-(3-indolyl)-1- amino-ethyl, S-keto-Z-pyrrolidinyl, S-pyrrolidyl and l-methyl-4-phenyl-4-piperidyl groups.
(f) Aralkenyl groups such as the phenylethenyl group.
(g) Hydroxyalkyl groups such as the hydroxymethyl and hydroxyethyl groups.
(h) Cycloalkyl-lower alkyl groups such as the cyclopentylpropyl and cyclohexylrnethyl groups.
(1) Alkynyl groups and particularly lower alkynyl groups such as the propargyl group.
(k) Groups in which represents a dicyclic glycolyl group including the benziloyl, phenylcyclohexyl glycolyl, phenylcyclopentyl glycolyl, 2-thienyl phenyl glycolyl and dicyclohexyl glycolyl groups. (I) Aminoalkyl groups such as aminomethyl, fl-arni noethyl, alpha-aminoethyl, 3-(methylmercapto)-laminopropyl, 4-methyl-l-aminobutyl, 3-hydroXy-laminopropyl and 3-methyl-3-hydroxy-l-ammopro- Py (m) Omega-carboxy-(amino)-alkyl groups such as Z-carboxy-l-aminoethyl, 3-carboxy-l-aminopropyl,
and 3-carboXy-3-amino-l-propyl. (n) Carboxyalkyl groups such as the carboxy-lower alkyl groups including the carboxyethyl group. (3) R is hydrogen or at least one nuclear substituent on the phenyl group such as a:
(a) Lower alkyl group such as methyl, ethyl, propyl and the like. (b) Lower alkoxy group such as methoxy, ethoxy,
and the like. Halogen such as bromine or chlorine. (d) The hydroxy group. (e) A lower alkylenedioxy group such as the 3,4-
methylene dioxy group. (f) Aryl group such as the phenyl group. (g) Aryloxy group such as the phenoxy group. (h) Aralkyl group as the benzyl or phenethyl group.
Some specific compounds which may be used as described are l-phenylmethyl-Z-acetyl hydrazine, l-phenylethyl-2-propionyl hydrazine, l-phenylpropyl-Z-benzoyl hydrazine, 1-phenylisopropyl-2-cyclohexanecarboxyl hydrazine, 1-p-chlorophenylmethyl-Z-phenylacetyl hydrazine, lp-methoxyphenylhexyl-Z-p-chlorophenylpropionyl hydrazine, 1-phenylisopropyl-Z-isonicotinyl hydrazine, l-phenylbutyl-Z-(Z-pyrrolecarboxyl)hydrazine, 1 phenyloctyl 2- nicotinyl hydrazine, 1-phenylethyl-2-(2-pyrazinylcarboxyl) hydrazine, l-o-methylphenylisopropyl-2-cinnamoyl hydrazine, 1 phenylisopropyl-Z-hydroxyacetyl hydrazine, lphenylethyl-Z-cyclohexylacetyl hydrazine, l-phenylmethyl- 2-acrylyl hydrazine, 1-phenylisopropyl-2-benziloyl hydrazine, 1-phenylethyl-2-dicyclohexyl glycolyl hydrazine, 1- phenylpropyl2-furanecarboxyl hydrazine, l-benzilyl-2- phenylisopropyl hydrazine, 1-(S-pyrrolidone)-2'-carboxyl- 2-benzyl hydrazine, l-glutamyl-Z-(alphaphenyl)-ethyl hydrazine, 1-benzoyl-Z-phenylisopropyl hydrazine, N-(S-pyrrolidone-Z-carboxyl)-N-(l phenyl-2-propyl) hydrazine, N-(S-L-glutamyl)-N-(l-phenyl-2-propyl) hydrazine, 1- nicotinyl-Z-phenylisopropyl hydrazine, 1-picolinyl-2- phenylisopropyl hydrazine and 1-palmitoyl-2-phenylisopropyl hydrazine.
The most potent monoamine oxidase inhibitors of Formula I are those in which Y has no more than three carbons between the phenyl and hydrazine moieties.
These l-phenylalkyl-2-acyl hydrazines have an etfect on the heart. The compounds are useful in the treatment of aperson in a'state of shock.
These compounds are hypotensor agents when administered to humans and thus are useful in the treatment of hypertension. In the dog, however, they raise the blood pressure.
Many of these compounds are many times more potent monoamine oxidase inhibitors than iproniazid. N- pyrrolidone-Z-carboxyl) N-(1-phenyl-2-propyl)-hydrazine is particularly active and, in addition, is faster acting in humans than iproniazid.
The compounds of this invention are useful for potentiating other therapeutic agents, such as phenothiazine tranquilizers like promazine and chloropromazine.
When a l-phenyl-Z-acyl hydrazine is administered to an animal followed by a barbiturate, the sedative action of the barbiturate is potentiated;
The compounds of this invention are themselves potentiated by chlorothiazide so that a greater hypotensor activity is obtained.
These compounds are also useful in treating angina pecteris.
These compounds in general are neutral rather than basic compounds. If there is an additional group of a basic nature present such as the compound of Example 2 following nontoxic acid addition salt such as the hydrochloride, hydrobrornide, phosphate, fumarate or sulfate may be readily prepared.
The l-phenylalkyl-Z-acyl hydrazines may be administered to animals and humans as pure compounds. It is advisable, however, to first combine one or more of the novel compounds with a suitable pharmaceutical carrier to attain a more satisfactory size to dosage relationship.
Pharmaceutical carriers which are liquid or solid may be used. The preferred liquid carrier is water. Flavoring materials may be included in the solutions as desired.
Solid pharmaceutical carriers such as starch, sugar talc and the like may be used to form powders. The powders may be used as such for direct administration to a patient or, instead, the powders may be added to suitable foods and liquids, including water, to facilitate administration.
The powders may also be used to make tablets, or to fill gelatin capsules. Suitable lubricants like magnesium stearate, binders such as gelatin, and disintegrating agents like sodium carbonate in combination with citric acid may be used to form the tablets.
Unit dosage forms such as tablets and capsules may contain any suitable predetermined amount of one or more of the l-phenylalkyl-Z-acyl hydrazines as a nontoxic acid addition salt and may be administered one or more at a time at regular intervals. Such unit dosage forms, however, should generally contain a cencentration of 0.1% to 10% by weight of one or more of the active hydrazines.
Dosages of from about 1 mg. to 50 mg. may be administered to obtain the stated activities. However, the recommended dosages are from 3 to 12 mg. daily. Larger dosages may be administered on an interrupted schedule but generally not more than 50 mg. and preferably not more than 25 mg. is administered daily.
A typical tablet may have the composition:
Mg. (1) l-isonicotinyl-2-phenylisopropyl hydrazine HCl 10 (2) Starch, U.S.P. 57 (3) Lactose, U.S.P. 73 (4) Talc, U.S.P. 9 (5) Stearic acid 6 Powders 1, 2 and 3 are slugged, then granulated, mixed with 4 and 5, and tableted.
Similarly, N- 5-pyrrolidone-Z-carboxyl) -N'-( l-phenyl- 2-propyl)-hydrazine may be used in this procedure to form tablets containing it as the active ingredient.
Capsules may be prepared by filling No. 3 hard gelatin capsules with the following ingredients, thoroughly mixed:
Mg. (1) l-acetyl-2-phenylethyl hydrazine HCl 5 (2) Lactose, U.S.P. 200 (3) Starch, U.S.P. 16 (4) Talc, U.S.P. 8
The oral route is preferred for administering the active l-phenylalkyl-Z-acyl hydrazines.
According to a further embodiment of this invention one or more of the l-phenylalkyl-2-acyl hydrazines is administered simultaneously with, or concomitantly to, the administration of either tryptophan and/or phenylalanine to an animal or human. Tryptophan passes the blood-brain barrier and is converted in the brain to serotonin. Serotonin is not administered directly since it cannot pass the blood-brain barrier. Similarly, phenylalanine passes the blood-brain barrier and is converted in the brain to norepinephrine. Norepinephrine itself will not pass the blood-brain barrier so it is not given directly. By the administration of an active l-phenylalkyl-Z-acyl hydrazine simultaneously with, or concomitantly to, either tryptophan or phenylalanine the monoamine oxadase inhibitory property of the hydrazine retards or prevents the degradation of serotonin and/or norepinephrine which 6 are produced in the brain from the said amino acids. The serotonin and norepinephrine levels are thus not only raised but are maintained at the increased level by the described treatment.
Any suitable amounts of tryptophan and/ or phenylalanine may be administered since these materials are nontoxic. One or more of these materials advisably combined with one or more of the active hydrazines into suitable pharmaceutical formulations.
This method of preparing the l-phenylalkyl-Z-acyl hydrazines comprises reacting the hydrazine with a phenylalkyl ketone or aldehyde to form a 1-ara1kylidenyl-2-acyl hydrazine and reducing the hydrazone to the desired l-phenylalkyl-Z-acyl hydrazines. This process may be represented as follows:
wherein Y, R and R have the significance previously assigned.
Some of the phenylalkyl ketones or aldehydes which may be used in this process are phenylacetaldehyde, phenylpropionaldehyde, phenylbutyraldehyde, phenylacetal, phenylvaleraldehyde, phenylethanone, phenylacetone, 1,3- diphenyl 2 propanone, phenylpentanone and p-chlorophenylbutanone and similar compounds containing one or more nuclear groups on the phenyl group, such as represented by R in the Formula I.
Representative of the acyl hydrazines which may be used in the process are'acetyl hydrazine, propionyl hydrazine, benzoyl hydrazine, cyclohexanecarboxyl hydrazine, phenylacetyl hydrazine, isonicotinyl hydrazine, pyrrolcarboxyl hydrazine, nicotinyl hydrazine, benziloyl hydrazine, dicyclohexylglycolyl hydrazine and the like.
Reaction between the phenylalkyl ketone or aldehyde and the acyl hydrazine is conveniently efiected by contacting the reactants in the presence of water or a lower alcohol. The reaction proceeds at room temperature although slightly elevated temperatures such as the reflux temperature may be employed to increase the rate of reaction.
Recovery of the intermediate aminoalkylidenyl hydrazine is conveniently effected by conventional methods. Thus, the product, generally an oil as the free base, may be salted out with an alkali metal hydroxide and extracted with a water immiscible organic solvent such as ether. The product is readily isolated by distillation under reduced pressure.
The intermediate hydrazones may be reduced to the corresponding hydrazines by use of a suitable reducing agent. Lithium alumirnun hydride may be used although catalytic hydrogenation is recommended. With lithium aluminum hydride, the reduction may be conveniently eflected by intimately combining the reactants in an inert organic solvent such as anhydrous ether, diox-ane, or tetrahydrofuran. Elevated temperatures such as the reflux temperature enhance the reaction. At reflux temperature, from 1 to 8 hours is usually suificient to substantially complete the reaction. After the reaction is terminated, water may be added to the mixture to decompose excess lithium aluminum hydride. To recover the product, the organic phase is separated and the aqueous residue extracted with the same solvent. The organic phase and extracts then may be combined, dried, and the product distilled.
Catalytic reduction is readily achieved using catalysts such as rhodium, platinum oxide, palladium and the like in solvents such as methanol, ethanol, tctrahydroturan,
water, ethyl acetate and dioxan. Raney nickel is not a particularly suitable catalyst since undue cleavage occurs. Hydrogen pressures of about 50 to 3000 p.s.i. may be used. The temperature of reduction may be room temperature of increased temperatures such as up to C.
Hydrazines, such as those named above, may be formed in this way.
The following examples illustrate the methods of making the compounds.
EXAMPLE 1 Z -1s0nic0tinyl-2-Phenylis0pr0pylidenyl-Hydrazine A mixture of 23.3 g. (0.17 mole) of isonicotinyl-hydrazinc and 45.6 (0.34 mole) of phenylacetone in 200 cc. of isopropanol was refluxed for six hours. After removal of the isopropanol by distillation in vacuo, a solid residue remained which was recrystallized from isopropan- 01. White crystals were obtained, M.P. 112l14 (3., yield, 31.0 (72%).
EXAMPLE 2 1-Is0nic0tinyZ-2-Phenylisopropyl Hydrazine and Hydrochloride A solution of 12.7 g. (0.05 mole) of l-isonicotinyl-Z- phenylisopropylidenyl hydrazine in cc. of methanol was hydrogenated on the Parr apparatus at room temperature and initial pressure of 60 lbs., using 100 mg. of platinum oxide as catalyst. The reduction was stopped at the end of two hours, when one mole-equivalent of hydrogen was used. The catalyst was filtered off through a Celite bed, .and the methanol was removed by distillation in vacuo. The syrupy residue was dissolved in cc. of isopropanol, and ethereal HCl was added to pH 1.0 to 2.0. White crystals were obtained which were recrystallized by dissolving them in 400 cc. of methanol and adding 500 cc. of isopropanol; M.P. 239240 C. dec., yield 14.0 g. (85% Analysis.-Calcd. for C H Cl N O: Cl, 21.60%; N, 12.80%. Found: Cl, 21.71%; N, 13.03%.
EXAMPLE 3 1-Benziloyl-2-Pltenylisopropylidenyl Hydmzz'ne C(OH)CONHN=C-(CH )-CH A mixture of 0.10 mole of benzilic acid hydrazide and 0.10 mole of phenylacetone in 200 cc. of tertiary butyl alcchol was refluxed for 4 hours, the solvent removed by distillation in vacuo. The residue contained this product.
EXAMPLE 4 1-Beizzil0yl-2- henylisopropyl Hydrazine C(OH)CONH-NHCH-(CH )CH A solution containing 0.078 mole of the isopropylidene derivative of Example 3 in cc. of methanol was subjected to hydrogenation with 150 mg. of platinum oxide at 60 lbs. of hydrogen. After the theoretical amount of hydrogen had been absorbed, the reaction was stopped, the catalyst removed by filtration and the product isolated as in Example 2. The hydrazide was a solid.
EXAMPLE 5 1 (5 -Pyrr0lid0ne -2 '-Carb0xyl2-Benzylidenyl H ydrazine 7 EXAMPLE 6 1 '-Pyrr0lidone) -2-Carboxyl] -2-Benzyl H ydrazine A methanol solution containing 0.10 mole of the benzylidene derivative of Example 5 was subjected to hydrogenation at 40 p.s.i. of hydrogen in the presence of 0.1 g. of platinum oxide catalyst. Hydrogenation was discontinued as soon as the theoretical amount of hydrogen had been absorbed, to prevent cleavage of the benzyl group. The catalyst was removed by filtration and the solvent removed by distillation. The residue was an oil which did not readily crystallize.
EXAMPLE 7 J-(S-Glutamyl)-2-(AIpl1a-Plzenyl)-Ethyl Hydrazine Ethyl glutamate was converted to the hydrazide in the usual manner. The hydrazide was reacted with acetophenone by mixing equirnolar quantities of glutamic acid hydrazide with acetophenone in methylisobutylcarbinol and refluxing the mixture for several hours. The solvent was removed by distillation in vacuo and the residue taken up in methanol. The methanol solution was subjected to hydrogenation in the usual manner being careful, however, to allow only the theoretical amount of hydrogen to be absorbed. The hydrogenation catalyst was removed by filtration and the filtrate concentrated in vacuo. The residual product was a low melting solid.
l-benzoyl hydrazine was reacted with l-phenyl-Z-propanone following the method of Example 1 and the resulting phenylisopropylidene derivative reduced catalytically as in Example 2 to yield the desired product.
EXAMPLE 9 S-Pyrrolz'done-Z-Carb0xylic Acid Hydrazz'de A mixture containing 15.6 g. (0.12 mole) of methyl S-pyrrolidone-Z-carboxylate, 10.3 g. of 85% hydrazine and 200 cc. of ethanol was refluxed for several hours, the ethanol removed by distillation and the residue crys tallized from a mixture of ethanol-ethyl acetate, yield 14.2 g. (91%), M.P.113115 C.
EXAMPLE 10 N-(5-Pyrr0lid01ze-2-Carboxyl) -N'-(1-Plzen l-2- Propylidenyl -Hydrazine A mixture of 37 g. (0.26 mole) of the hydrazide from Example 9 and 67 g. (0.50 mole) of phenylacetone, 100 cc. of isopropanol and 75 cc. of ethanol was refluxed for 6 hours. The solvents were removed by distillation and the residue recrystallized from ethanol, yield 62 g. (92%); M.P. 153 C.
8 Analysis.-Calcd. for C H N O N, 16.20. Found: N, 15.35.
EXAMPLE 11 The acyl hydrazone (12.95 g.) of Example 10 was reduced with 0.50 g. of PtO in 200 cc. of ethanol at 60 lbs. of hydrogen. The solvent was removed by distillation and the residue crystallized from ether. The solid was recrystallized from acetonitrile, M.P. 160 C.
Analysis.Calcd. for C H N O N, 16.08. Found: N, 15.95.
EXAMPLE 12 N-(5-L-Glutamyl)-N'-(1-Phenyl-2-Propylidenyl)- Hydrazine To 16.1 g. (0.10 mole) of 5-1-glutamic acid hydrazide dissolved in 200 cc. of water at 35 C. was added 13.4 g. (0.10) mole) of phenylacetone and the mixture stirred for 3 hours. The white precipitate was collected by filtration, yield 20 g. (72%); M.P. 173 C.
Arzalysis.Calcd. for C H N O N, 15.15. Found: N, 14.90.
EXAMPLE 13 N (5 -L-Glutamyl -N 1 -Phenyl-2-Pr0pyl -H ydrazine The compound of Example 12 was subjected to hydrogenation in the manner described in Example 11; yield M.P. 174175 C.
Analysis.Calcd. for C I-1 N 0 N, 15.05. Found: N, 15.35.
EXAMPLE 14 1-Nicotinyl-2-Phenylis0pr0pylidenyl H ydrazine EXAMPLE 16 l-Pic0linyl-2-Phenylisopropylidenyl H ydrazine This compound was prepared from picolinic acid hydrazide and 1-phenyl-2-propanone by the procedure of Example 1; yield M.P. 145146 C.
Analysis.Calcd. fOI' C I N202: N, 16.59. Found: N, 16.20.
EXAMPLE 17 1-Pic0linyl-2-Phenylis0pr0pyl H ydrazine The acyl hydrazone of Example 16 was reduced by the method outlined in Example 2.
The dihydrochloride salt melted at 189-190 C.
Analysis.-Calcd. for C H Cl N O: Cl, 21.60; N, 12.80. Found: Cl, 21.35; N, 12.60.
EXAMPLE l8 1-Palmitoyl-2-Phenylisopropylidenyl Hydrazine This compound was prepared from palmitoic acid hydrazide and 1-phenyl-2-propanone by the procedure of Example 1, yield 90%, M.P. 7576 C.
9 Analysis.-Calcd. for C H N O: N, 7.24. Found: N, 7.08.
EXAMPLE 19 l -Palmitoyl-Z-Phenylisopropyl H ydrazine The acyl hydrazone of Example 18 was reduced by the method outlined in Example 2; M.P. 81-82 C.
Analysis.-Calcd. for C H N O: N, 7.21. Found: N, 7.57.
Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included Within the scope of the appended claims.
What is claimed is:
1. A compound of the formula wherein R is a lower alkylene radical.
2. 1-(5-g1utamy1) -2-(alpha-phenyl)-1ower alkyl hydrazlne.
1 0 3. 1-(S-glutamyl)-2-(a1pha-pheny1)-ethy1 hydrazine. 4. N-(5-L-glutamy1)-N-( 1-phenyl-2-propyl)-hydrazine.
References Cited in the file of this patent UNITED STATES PATENTS OTHER REFERENCES Shchukina et al.: Chem. Abstracts, Vol. 46, col. 10431-2 (1952). (Abstract of Doklady Akad. Nauk U.S.S.R., vol. 84, 981-4 (1952).
Fox: J. Org. Chem, vol. 20, November 1, pages 60-69 (1955).
Claims (1)
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3288848A (en) * | 1964-12-21 | 1966-11-29 | Upjohn Co | Alpha-amino dibasic acid hydrazides |
US3297530A (en) * | 1958-12-23 | 1967-01-10 | Ici Ltd | Antidepressant compositions and methods of using same |
US3549767A (en) * | 1966-12-16 | 1970-12-22 | Geigy Chem Corp | Method of controlling insects and acarinae,employing certain acylated hydrazones and hydrazines |
US3888840A (en) * | 1973-02-07 | 1975-06-10 | American Home Prod | Novel hydrazinocarboxamide derivatives and preparation thereof |
US4162329A (en) * | 1977-03-22 | 1979-07-24 | Bayer Aktiengesellschaft | Combating fungi with dicarboxylic acid mono-arylhydrazides |
US4201785A (en) * | 1978-02-27 | 1980-05-06 | Sandoz Inc. | Cyclopropanyl-bearing hydrazides |
US4229463A (en) * | 1978-02-27 | 1980-10-21 | Sandoz, Inc. | Unsaturated fatty acid hydrazides |
US4925832A (en) * | 1986-07-16 | 1990-05-15 | Minnesota Mining And Manufacturing Company | Silver halide photographic light-sensitive systems |
US5229038A (en) * | 1990-09-12 | 1993-07-20 | Fuji Photo Film Co., Ltd. | Organic nonlinear optical material and method of converting the wavelength of light using said material |
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US2149279A (en) * | 1934-07-07 | 1939-03-07 | Merck & Co Inc | Derivatives of pyrazine carboxylic acid and processes for their production |
US2176063A (en) * | 1936-09-01 | 1939-10-17 | Merck & Co Inc | Derivatives of pyrazine carboxylic acid and processes for their production |
US2383134A (en) * | 1943-09-18 | 1945-08-21 | American Cyanamid Co | Preparation of symmetrical diaryl hydrazines |
US2688040A (en) * | 1952-02-27 | 1954-08-31 | Du Pont | Manufacture of hydrazobenzene compounds |
US2784141A (en) * | 1954-05-13 | 1957-03-05 | Merck & Co Inc | Tranquilizing composition comprising alkyl aminoethyl esters of benzilic acid and salts thereof |
US2804422A (en) * | 1954-12-29 | 1957-08-27 | Wm S Merrell Co | Tranquilizing composition comprising alpha phenyl, alpha-(4-piperidyl)-benzyl alcohol and method of using same |
US2923713A (en) * | 1952-03-07 | 1960-02-02 | Hoffmann La Roche | Isonicotinic acid, benzyl and p-methoxybenzyl hydrazides |
US2923714A (en) * | 1958-02-13 | 1960-02-02 | Hoffmann La Roche | 1-picolinoyl-2-benzyl hydrazine and salts |
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US2149279A (en) * | 1934-07-07 | 1939-03-07 | Merck & Co Inc | Derivatives of pyrazine carboxylic acid and processes for their production |
US2176063A (en) * | 1936-09-01 | 1939-10-17 | Merck & Co Inc | Derivatives of pyrazine carboxylic acid and processes for their production |
US2383134A (en) * | 1943-09-18 | 1945-08-21 | American Cyanamid Co | Preparation of symmetrical diaryl hydrazines |
US2688040A (en) * | 1952-02-27 | 1954-08-31 | Du Pont | Manufacture of hydrazobenzene compounds |
US2923713A (en) * | 1952-03-07 | 1960-02-02 | Hoffmann La Roche | Isonicotinic acid, benzyl and p-methoxybenzyl hydrazides |
US2784141A (en) * | 1954-05-13 | 1957-03-05 | Merck & Co Inc | Tranquilizing composition comprising alkyl aminoethyl esters of benzilic acid and salts thereof |
US2804422A (en) * | 1954-12-29 | 1957-08-27 | Wm S Merrell Co | Tranquilizing composition comprising alpha phenyl, alpha-(4-piperidyl)-benzyl alcohol and method of using same |
US2923714A (en) * | 1958-02-13 | 1960-02-02 | Hoffmann La Roche | 1-picolinoyl-2-benzyl hydrazine and salts |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3297530A (en) * | 1958-12-23 | 1967-01-10 | Ici Ltd | Antidepressant compositions and methods of using same |
US3288848A (en) * | 1964-12-21 | 1966-11-29 | Upjohn Co | Alpha-amino dibasic acid hydrazides |
US3549767A (en) * | 1966-12-16 | 1970-12-22 | Geigy Chem Corp | Method of controlling insects and acarinae,employing certain acylated hydrazones and hydrazines |
US3888840A (en) * | 1973-02-07 | 1975-06-10 | American Home Prod | Novel hydrazinocarboxamide derivatives and preparation thereof |
US4162329A (en) * | 1977-03-22 | 1979-07-24 | Bayer Aktiengesellschaft | Combating fungi with dicarboxylic acid mono-arylhydrazides |
US4201785A (en) * | 1978-02-27 | 1980-05-06 | Sandoz Inc. | Cyclopropanyl-bearing hydrazides |
US4229463A (en) * | 1978-02-27 | 1980-10-21 | Sandoz, Inc. | Unsaturated fatty acid hydrazides |
US4925832A (en) * | 1986-07-16 | 1990-05-15 | Minnesota Mining And Manufacturing Company | Silver halide photographic light-sensitive systems |
US5229038A (en) * | 1990-09-12 | 1993-07-20 | Fuji Photo Film Co., Ltd. | Organic nonlinear optical material and method of converting the wavelength of light using said material |
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